A. 2-(2,2-Dimethylpropanoyl)-1,3-dithiane. To
43.0 g (0.358 mol) of 1,3-dithiane(Note 1) at 0°C under a nitrogen atmosphere is added
396 mL of a 1 M solution of sodium hexamethyldisilazide in tetrahydrofuran (THF)(Note 2) and (Note 3). The resulting yellow solution is allowed to reach room temperature and then stirred at room temperature for 1 hr. The solution is cooled to 0°C, and
172 mL of a 2.5 M solution of butyllithium in hexanes(Note 4) is added. The reaction mixture is allowed to warm to room temperature and then stirred at room temperature for 30 min. Ethyl 2,2-dimethylpropanoate (65.0 mL, 0.427 mol)(Note 5) is added, and the mixture is stirred at room temperature for 2.5 hr. An aqueous saturated solution of ammonium chloride (200 mL) is added, and the aqueous phase is extracted three times with
200 mL of dichloromethane(Note 6). The combined organic extracts are washed with 100 mL of water and dried over anhydrous magnesium sulfate. The solvents are removed under reduced pressure to give a yellow solid. Repeated trituration with petroleum ether 40-60°C (Note 7) followed by filtration gives 51.0-55.1 g (70-75%) of 2-(2,2-dimethylpropanoyl)-1,3-dithiane as colorless needles, mp 97-99°C(Note 8).

B. anti- and syn-1S-(2,2-Dimethylpropanoyl)-1,3-dithiane 1-oxide. (+)-[(8,8-Dimethoxycamphoryl)sulfonyl]oxaziridine (51.0 g, 0.176 mol)(Note 9) is added to a cooled, stirred solution of
36.0 g (0.176 mol) of 2-(2,2-dimethylpropanoyl)-1,3-dithiane in
1000 mL of carbon tetrachloride(Note 10) at 0°C. The reaction mixture is allowed to reach room temperature, and stirring is continued at room temperature for a further 48 hr. The reaction mixture is filtered to remove the bulk of the (+)-[(8,8-dimethoxycamphoryl)sulfonyl]imine, and the filtrate is evaporated to dryness under reduced pressure. The residue is purified by passage through a short column of silica gel using dichloromethane as initial eluant to remove residual (+)-[(8,8-dimethoxycamphoryl)sulfonyl]imine. The column is then flushed with ethyl acetate to give 29.8-33.5 g (77-86%) of an ca. 3:1 mixture of anti- and syn-1S-(2,2-dimethylpropanoyl)-1,3-dithiane 1-oxide as a colorless crystalline solid, mp 103-105°C(Note 11).

C. (1S)-(−)-1,3-Dithiane 1-oxide. A mixture of anti- and syn-1S-2-(2,2-dimethylpropanoyl)-1,3-dithiane 1-oxide (33 g, 0.150 mol) is dissolved in
500 mL of ethanol(Note 12), and
200 mL of aqueous 5%
sodium hydroxide is added. The mixture is heated under reflux for 24 hr. The mixture is allowed to cool, and
500 mL of dichloromethane is added. The organic layer is separated, and the aqueous phase is extracted four times, with
100 mL of dichloromethane. The combined organic extracts are dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give a beige solid. The solid is triturated with diethyl ether to give 13 g (64%) of 1S-(−)-1,3-dithiane 1-oxide as a colorless solid, mp 90-92°C(Note 13) and (Note 14).

2. Notes

1.
1,3-Dithiane was stored in a desiccator over self-indicating silica gel.

2.
Tetrahydrofuran was distilled under nitrogen from the benzophenone ketyl radical.

3.
Sodium hexamethyldisilazide [sodium bis(trimethylsilyl)amide] was purchased from the Aldrich Chemical Company, Inc., in 100- or 800-mL bottles as a 1 M solution in tetrahydrofuran. Glassware used for moisture sensitive reactions was dried at 180°C and allowed to cool in a desiccator over self-indicating silica gel. Reactions were carried out under a slight positive static pressure of argon.

4.
Butyllithium was purchased from the Aldrich Chemical Company, Inc.
, in 800-mL bottles as a 2.5 M solution in hexanes; the molarity was determined by titration against a solution of diphenylacetic acid.

5.
Commercially available reagents were used as supplied unless otherwise stated.

14.
The checkers obtained the product in about 54% yield and found flash chromatography to be more effective in its purification. This was accomplished using a 16-cm × 5-cm column of silica gel and CHCl3/MeOH (96:4) as the eluant. With collection of ca. 50-mL fractions, the product was observed in fractions 12-21. Visualization of the product was accomplished by TLC (product Rf = 0.4 in CHCl3/MeOH 96:4, anisaldehyde stain).

15.
The checkers noted that complete oxidation typically required ca. 6-7 hr and recommend checking the progress of the reaction in the following way: a 1-mL aliquot is removed from the organic layer, diluted with 2 mL of methylene chloride, and analyzed by TLC eluting with methylene chloride (I2 visualization); imine Rf = 0.34, oxaziridine Rf = 0.51

The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.

These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.

3. Discussion

Non-racemic chiral sulfoxides have become important as sources of chirality for asymmetric carbon-carbon bond formation.4 For example, we have developed 1,3-dithiane 1-oxide (DiTOX) units as effective moieties for stereocontrol of a range of carbonyl group reactions, including enolate alkylation and amination, Mannich reaction, reduction, and heterocycloaddition.5 While we have been able to prepare several 2-monosubstituted6 and 2,2-disubstituted-1,3-dithiane 1-oxides7 in high enantiomeric excesses (ee) on scales of a few grams, we had difficulty until recently in preparing the parent compound, 1,3-dithiane 1-oxide, with very high ee in quantities of more than ca. 5 g.8 Enantiomerically pure 1,3-dithiane 1-oxide has previously been prepared via adducts with (+)-camphor,9 and, by ourselves, using modified Sharpless oxidation techniques.8,10,11

We have recently reported that [(8,8-dimethoxycamphoryl)sulfonyl]oxaziridine is a particularly effective reagent for asymmetric sulfide oxidation, especially in non-aryl sulfide substrates.3 Here we report a three-step chemical synthesis of 1,3-dithiane 1-oxide with very high ee that is based upon such an oxidation as the key step. The procedure is effective for production of multigram quantities of material of either absolute configuration. The sequence is illustrated for the preparation of 1S-(−)-1,3-dithiane 1-oxide.

The route is based upon an acylation-oxidation-deacylation sequence, with commercially available, inexpensive 1,3-dithiane employed as the starting material. 2-Acyl-1,3-dithianes have proved to be particularly effective substrates for asymmetric oxidation in our hands,8,10,3,12 and as 2-(2,2-dimethylpropanoyl)-1,3-dithiane undergoes this asymmetric oxidation most efficiently (ca. 90% ee), it was chosen as the intermediate.

References and Notes

Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Oxford Street, Liverpool L69 3BX, England. This investigation has enjoyed the support of the EPSRC and Glaxo Research & Development (CASE award to JPH); present address: Department of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, England

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